Experimentally Guided Computational Model Discovers Important Elements for Social Behavior in Myxobacteria

Identifying essential factors in cellular interactions and organized movement of cells is important in predicting behavioral phenotypes exhibited by many bacterial cells. We chose to study Myxococcus xanthus, a soil bacterium whose individual cell behavior changes while in groups, leading to spontaneous formation of aggregation center during the early stage of fruiting body development. In this paper, we develop a cell-based computational model that solely relies on experimentally determined parameters to investigate minimal elements required to produce the observed social behaviors in M. xanthus. The model verifies previously known essential parameters and identifies one novel parameter, the active turning, which we define as the ability and tendency of a cell to turn to a certain angle without the presence of any obvious external factors. The simulation is able to produce both gliding pattern and spontaneous aggregation center formation as observed in experiments. The model is tested against several known M. xanthus mutants and our modification of parameter values relevant for the individual mutants produces good phenotypic agreements. This outcome indicates the strong predictive potential of our model for the social behaviors of uncharacterized mutants and their expected phenotypes during development

Biologic Phenotyping of the Human Small Airway Epithelial Response to Cigarette Smoking

BACKGROUND: The first changes associated with smoking are in the small airway epithelium (SAE). Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a "COPD-like" SAE transcriptome. METHODOLOGY/PRINCIPAL FINDINGS: SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes. Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (I(SAE)), with healthy smokers grouped into "high" and "low" responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker. Smokers demonstrated significant variability in SAE transcriptome with I(SAE) ranging from 2.9 to 51.5%. While the SAE transcriptome of "low" responder healthy smokers differed from both "high" responders and smokers with COPD, the transcriptome of the "high" responder healthy smokers was indistinguishable from COPD smokers. CONCLUSION/SIGNIFICANCE: The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria. This identifies a group of smokers with a "COPD-like" SAE transcriptome

Population weighted raster maps can communicate findings of social audits: examples from three continents

<p>Abstract</p> <p>Background</p> <p>Maps can portray trends, patterns, and spatial differences that might be overlooked in tabular data and are now widely used in health research. Little has been reported about the process of using maps to communicate epidemiological findings.</p> <p>Method</p> <p>Population weighted raster maps show colour changes over the study area. Similar to the rasters of barometric pressure in a weather map, data are the health occurrence – a peak on the map represents a higher value of the indicator in question. The population relevance of each sentinel site, as determined in the stratified last stage random sample, combines with geography (inverse-distance weighting) to provide a population-weighted extension of each colour. This transforms the map to show population space rather than simply geographic space.</p> <p>Results</p> <p>Maps allowed discussion of strategies to reduce violence against women in a context of political <it>sensitivity</it> about quoting summary indicator figures. <it>Time-series maps</it> showed planners how experiences of health services had deteriorated despite a reform programme; where in a country HIV risk behaviours were improving; and how knowledge of an economic development programme quickly fell off across a region. <it>Change maps</it> highlighted where indicators were improving and where they were deteriorating. Maps of <it>potential impact of interventions</it>, based on multivariate modelling, displayed how partial and full implementation of programmes could improve outcomes across a country. <it>Scale</it> depends on context. To support local planning, district maps or local government authority maps of health indicators were more useful than national maps; but multinational maps of outcomes were more useful for regional institutions. Mapping was useful to illustrate in which districts enrolment in religious schools – a <it>rare occurrence</it> - was more prevalent.</p> <p>Conclusions</p> <p>Population weighted raster maps can present social audit findings in an accessible and compelling way, increasing the use of evidence by planners with limited numeracy skills or little time to look at evidence. Maps complement epidemiological analysis, but they are not a substitute. Much less do they substitute for rigorous epidemiological designs, like randomised controlled trials.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells

Changes in cell adhesion and migration in the tumor microenvironment are key in the initiation and progression of metastasis. R-Ras is one of several small GTPases that regulate cell adhesion and migration on the extracellular matrix, however the mechanism has not been completely elucidated. Using a yeast two-hybrid approach we sought to identify novel R-Ras binding proteins that might mediate its effects on integrins.We identified Filamin A (FLNa) as a candidate interacting protein. FLNa is an actin-binding scaffold protein that also binds to integrin β1, β2 and β7 tails and is associated with diverse cell processes including cell migration. Indeed, M2 melanoma cells require FLNa for motility. We further show that R-Ras and FLNa interact in co-immunoprecipitations and pull-down assays. Deletion of FLNa repeat 3 (FLNaΔ3) abrogated this interaction. In M2 melanoma cells active R-Ras co-localized with FLNa but did not co-localize with FLNa lacking repeat 3. Thus, activated R-Ras binds repeat 3 of FLNa. The functional consequence of this interaction was that active R-Ras and FLNa coordinately increased cell migration. In contrast, co-expression of R-Ras and FLNaΔ3 had a significantly reduced effect on migration. While there was enhancement of integrin activation and fibronectin matrix assembly, cell adhesion was not altered. Finally, siRNA knockdown of endogenous R-Ras impaired FLNa-dependent fibronectin matrix assembly.These data support a model in which R-Ras functionally associates with FLNa and thereby regulates integrin-dependent migration. Thus in melanoma cells R-Ras and FLNa may cooperatively promote metastasis by enhancing cell migration

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

The landscape of recombination in African Americans

Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10−245). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9

20th Century Atmospheric Deposition and Acidification Trends in Lakes of the Sierra Nevada, California, USA

We investigated multiple lines of evidence to determine if observed and paleo-reconstructed changes in acid neutralizing capacity (ANC) in Sierra Nevada lakes were the result of changes in 20th century atmospheric deposition. Spheroidal carbonaceous particles (SCPs) (indicator of anthropogenic atmospheric deposition) and biogenic silica and δ(13)C (productivity proxies) in lake sediments, nitrogen and sulfur emission inventories, climate variables, and long-term hydrochemistry records were compared to reconstructed ANC trends in Moat Lake. The initial decline in ANC at Moat Lake occurred between 1920 and 1930, when hydrogen ion deposition was approximately 74 eq ha(-1) yr(-1), and ANC recovered between 1970 and 2005. Reconstructed ANC in Moat Lake was negatively correlated with SCPs and sulfur dioxide emissions (p = 0.031 and p = 0.009). Reconstructed ANC patterns were not correlated with climate, productivity, or nitrogen oxide emissions. Late 20th century recovery of ANC at Moat Lake is supported by increasing ANC and decreasing sulfate in Emerald Lake between 1983 and 2011 (p &lt; 0.0001). We conclude that ANC depletion at Moat and Emerald lakes was principally caused by acid deposition, and recovery in ANC after 1970 can be attributed to the United States Clean Air Act